Project Summary/Abstract The objective of the proposed studies is to determine whether a novel anti-inflammatory lignan arctigenin will enhance the chemopreventive effect of green tea (GT) and quercetin (Q) in mouse models, and to identify the underlying mechanisms. GT and its bioactive components GT polyphenols (GTPs) are promising agents in the prevention of prostate cancer. However, the low bioavailability of GTPs limits the success of GT in humans. My previous cell culture and mouse studies demonstrated that the anti-cancer activity of GT can be significantly increased by combination with Q, a natural methylation inhibitor from onions and apples. The combination treatment of Q with GT increases the tissue concentrations of GTPs and decreases the conversion of GTPs to their less bioactive methyl metabolites. Further, we demonstrated in vitro that the combination of very low dose of arctigenin, a novel anti-inflammatory compound mainly from the seed of the herb Arctium lappa, with GT and Q synergistically enhanced the anti-proliferative effect of GT+Q by 2-3 fold in androgen-dependent LNCaP cells. Mechanistic investigations revealed an increase in apoptosis and in inhibition of PI3K/Akt and androgen receptor (AR) pathways by the combination treatment compared to individual compound. A similar pattern in anti-proliferation was also observed in pre-malignant prostate WPE1-NA22 cells with the combination treatment. The proposed project will determine whether this synergistic effect of the combination also occurs in vivo in mouse models. The specific aims include: 1) To determine whether co-treatment of arctigenin with GT and Q will enhance the chemopreventive activity of GT and Q in prostate specific PTEN knockout mice using tumor volume and tumor stage as study endpoints; 2) To validate in vivo the molecular mechanisms responsible for the combined effect of GT, Q and arctigenin with focus on the PI3K/Akt and AR pathways in tumor tissues. The proposed project will make significant contributions to clinical practice by providing a highly effective non-toxic regimen to enhance chemoprevention of prostate cancer at physiologically achievable concentrations of natural compounds. In addition to their direct activity to inhibit carcinogenesis, these natural compounds provide health benefits in prevention and treatment of risk factors of prostate cancer such as obesity and type 2 diabetes.